The entorhinal cortex (EC) is one of the most vulnerable brain regions that is attacked during the early stage of Alzheimer's disease (AD). Here, we report that the synaptic terminals of pyramidal neurons in the EC layer II (ECII ) directly innervate CA1 parvalbumin (PV) neurons (CA1 ) and are selectively degenerated in AD mice, which exhibit amyloid-β plaques similar to those observed in AD patients. A loss of ECII -CA1 synapses disables the excitatory and inhibitory balance in the CA1 circuit and impairs spatial learning and memory. Optogenetic activation of ECII using a theta burst paradigm rescues ECII -CA1 synaptic defects and intercepts the decline in spatial learning and memory. These data reveal a novel mechanism of memory loss in AD mice via the selective degeneration of the ECII -CA1 pathway.